Abstract PO-127: A uPA/uPAR axis in both the tumor cell and stromal compartment drives PDAC disease progression

2021 ◽  
Author(s):  
Yi Yang ◽  
Sara R. Abrahams ◽  
Aditi Kothari ◽  
Harshi Matada ◽  
Keely Davey ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Disease Progression ◽  
Stromal Compartment

scholarly journals Loss of cIAP1 in Endothelial Cells Limits Metastatic Extravasation through Tumor-Derived Lymphotoxin Alpha

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 599
Author(s):  
Lazaros Vasilikos ◽  
Kay Hänggi ◽  
Lisanne M. Spilgies ◽  
Samanta Kisele ◽  
Stefanie Rufli ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Advanced Disease ◽  
Disease Stage ◽  
Stromal Compartment ◽  
Tumor Load ◽  
Smac Mimetics ◽  
Advanced Disease Stage ◽  
Lymphotoxin Alpha ◽  
Open Question

In this study, we determined whether Smac mimetics play a role in metastasis, specifically in circulation, tumor extravasation and growth in a metastatic site. Reports suggest inducing the degradation of IAPs through use of Smac mimetics, alters the ability of the tumor cell to metastasize. However, a role for the immune or stromal compartment in affecting the ability of tumor cells to metastasize upon loss of IAPs has not been defined. To address this open question, we utilized syngeneic tumor models in a late-stage model of metastasis. Loss of cIAP1 in the endothelial compartment, rather than depletion of cIAP2 or absence of cIAP1 in the hematopoietic compartment, caused reduction of tumor load in the lung. Our results underline the involvement of the endothelium in hindering tumor cell extravasation upon loss of cIAP1, in contrast to the immune compartment. Endothelial specific depletion of cIAP1 did not lead to cell death but resulted in an unresponsive endothelium barrier to permeability factors causing a decrease in tumor cell extravasation. Surprisingly, lymphotoxin alpha (LTA), and not TNF, secreted by the tumor cells, was critical for the extravasation. Using TCGA, we found high LTA mRNA expression correlated with decreased survival in kidney carcinoma and associated with advanced disease stage. Our data suggest that Smac mimetics, targeting cIAP1/2, reduce metastasis to the lung by inhibiting tumor cell extravasation.

Analysis of VH Genes in Follicular and Diffuse Lymphoma Shows Ongoing Somatic Mutation and Multiple Isotype Transcripts in Early Disease With Changes During Disease Progression

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4292-4299 ◽  
Author(s):  
Christian H. Ottensmeier ◽  
Andrew R. Thompsett ◽  
Delin Zhu ◽  
Bridget S. Wilkins ◽  
John W. Sweetenham ◽  
...  
Keyword(s):  
Tumor Cell ◽  
B Cell ◽  
Disease Progression ◽  
Somatic Mutations ◽  
B Cell Lymphoma ◽  
Early Disease ◽  
Large B Cell Lymphoma ◽  
Vh Gene ◽  
Vh Genes ◽  
Tumor Cell Behavior

Investigations of VH gene mutational patterns in B-cell tumors are often performed at an arbitrary time point of disease. To assess the effects of disease progression, tumor-derived VHgenes have been monitored from presentation through treatment and relapse in one patient with follicle center lymphoma (FCL), and two patients with primary diffuse large B-cell lymphoma (DLCL). The patient with FCL and one patient with DLCL both achieved clinical remission, although this was only partial in the FCL. However, both subsequently relapsed, and the second patient with DLCL was refractory to radiotherapy and chemotherapy. In each case, the tumor-derived VH sequence was identified, and the CDR3 “clonal signature” was used to track tumor cell sequences in subsequent biopsies. All cases showed somatic mutations, with intraclonal heterogeneity evident at presentation, and some sequences were aberrant. The VH sequences of the DLCL which responded to treatment became homogeneous at relapse. The sequences of both the FCL and the refractory DLCL remained heterogeneous. In all cases, transcripts of multiple Ig isotypes could be identified, and there was immunophenotypic evidence for expression of several Ig isotypes. The case of refractory DLCL had identifiable transcripts from IgM, IgD, IgA, IgG, and IgE, but appeared to lose the ability to produce alternative isotype transcripts and protein at the late stage of disease. These cases indicate that VH gene analysis can be used to probe tumor cell behavior in cases of lymphoma and that perturbations caused by therapy and disease progression can occur.

scholarly journals Tumor Cell–Independent Estrogen Signaling Drives Disease Progression through Mobilization of Myeloid-Derived Suppressor Cells

2016 ◽  
Vol 7 (1) ◽  
pp. 72-85 ◽  
Author(s):  
Nikolaos Svoronos ◽  
Alfredo Perales-Puchalt ◽  
Michael J. Allegrezza ◽  
Melanie R. Rutkowski ◽  
Kyle K. Payne ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Disease Progression ◽  
Suppressor Cells ◽  
Estrogen Signaling ◽  
Myeloid Derived Suppressor Cells

scholarly journals Stable Differences in Intrinsic Mitochondrial Membrane Potential of Tumor Cell Subpopulations Reflect Phenotypic Heterogeneity

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Michele A. Houston ◽  
Leonard H. Augenlicht ◽  
Barbara G. Heerdt
Keyword(s):  
Membrane Potential ◽  
Tumor Cell ◽  
Disease Progression ◽  
Mitochondrial Membrane Potential ◽  
Mammary Tumor ◽  
Mitochondrial Membrane ◽  
Cell Populations ◽  
Mammary Tumor Cell ◽  
Colonic Tumor ◽  
Primary Mammary Tumor

Heterogeneity among cells that constitute a solid tumor is important in determining disease progression. Our previous work established that, within a population of metastatic colonic tumor cells, there are minor subpopulations of cells with stable differences in their intrinsic mitochondrial membrane potential (ΔΨm), and that these differences in ΔΨm are linked to tumorigenic phenotype. Here we expanded this work to investigate primary mammary, as well as colonic, tumor cell lines. We show that within a primary mammary tumor cell population, and in both primary and metastatic colonic tumor cell populations, there are subpopulations of cells with significant stable variations in intrinsic ΔΨm. In each of these 3 tumor cell populations, cells with relatively higher intrinsic ΔΨm exhibit phenotypic properties consistent with promotion of tumor cell survival and expansion. However, additional properties associated with invasive potential appear in cells with higher intrinsic ΔΨm only from the metastatic colonic tumor cell line. Thus, it is likely that differences in the intrinsic ΔΨm among cells that constitute primary mammary tumor populations, as well as primary and metastatic colonic tumor populations, are markers of an acquired tumor phenotype which, within the context of the tumor, influence the probability that particular cells will contribute to disease progression.

Evaluating biomarkers in metastatic castration-resistant prostate cancer patients treated with enzalutamide: PSA, circulating tumor cell counts, AR-V7 status and radiographic progression.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17569-e17569
Author(s):  
Shruti U. Gandhy ◽  
Fatima Karzai ◽  
Jennifer L. Marte ◽  
Marijo Bilusic ◽  
Sheri McMahon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Cell ◽  
Disease Progression ◽  
Median Time ◽  
Circulating Tumor Cell ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Cell Counts

e17569 Background: Enzalutamideis ahighly effective treatment in metastatic castration resistant prostate cancer (mCRPC). Although Prostate Cancer Working Group (PCWG) guidelines recommend continuing treatment until radiographic/clinical progression (rPD/cPD), many patients discontinue therapy for rising PSA alone. Methods: We conducted an open label, randomized phase 2 trial in mCRPC patients untreated with docetaxel, abiraterone, or enzalutamide, comparing enzalutamide alone or in combination with PROSTVAC, a therapeutic cancer vaccine designed to induce an anti-tumor immune response. The study discontinued accrual after planned interim analysis indicated no difference in progression between the two arms. Patients were followed beyond 1st of 3 confirmed PSA rises until rPD. 49 patients were analyzed for Circulating Tumor Cell (CTC) count and AR-V7 status at 1st PSA rise and at rPD/cPD or last follow up. Results: 57 patients were enrolled with median follow up time of 55.4 mo. 49/57 (86%) patients had rising PSA; median time to 1st PSA rise for all patients was 6.4 mo (95% CI: 3.7-11.0 mo) after starting enzalutamide. 38/57 (67%) patients had progressive disease (majority with rPD; 1/38 (3%) with cPD); median time to progression for all patients was 23.3 mo (95% CI: 16.1-27.8 mo). 5 patients tested positive for AR-V7 within 30 days of rPD. In patients who experienced rPD/cPD, CTCs were detected in 11/24 (46%) samples taken at rPD vs. in only 3/24 (13%) samples taken at rising PSA. CTC counts were higher at rPD compared to samples taken at rising PSA (P = 0.004, Wilcoxon unpaired test). Of the 7 patients still being treated (median time on drug = 4.2 yrs), 2 experienced rising PSA; however none of the patients had detectable CTCs at a median of 30 days from last follow up. Conclusions: These data suggest that a rising PSA may not be a warning of near-term clinically significant disease progression in mCRPC patients treated with enzalutamide, given the 17-month difference between the first rise in PSA and ultimate rPD/cPD seen in this analysis. Further, CTCs and AR-V7 status associate strongly with rPD but not with rising PSA, adding biological rationale to the hypothesis that CTC counts and AR-V7 status are associated with disease progression. Collectively, these data highlight the need to continue to educate patients and providers on PCWG criteria for progression and appropriately-timed utilization of both therapies and diagnostic tests to maximize drug efficacy in mCRPC. Clinical trial information: NCT01867333 .

Analysis of VH Genes in Follicular and Diffuse Lymphoma Shows Ongoing Somatic Mutation and Multiple Isotype Transcripts in Early Disease With Changes During Disease Progression

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4292-4299 ◽  
Author(s):  
Christian H. Ottensmeier ◽  
Andrew R. Thompsett ◽  
Delin Zhu ◽  
Bridget S. Wilkins ◽  
John W. Sweetenham ◽  
...  
Keyword(s):  
Tumor Cell ◽  
B Cell ◽  
Disease Progression ◽  
Somatic Mutations ◽  
B Cell Lymphoma ◽  
Early Disease ◽  
Large B Cell Lymphoma ◽  
Vh Gene ◽  
Vh Genes ◽  
Tumor Cell Behavior

Abstract Investigations of VH gene mutational patterns in B-cell tumors are often performed at an arbitrary time point of disease. To assess the effects of disease progression, tumor-derived VHgenes have been monitored from presentation through treatment and relapse in one patient with follicle center lymphoma (FCL), and two patients with primary diffuse large B-cell lymphoma (DLCL). The patient with FCL and one patient with DLCL both achieved clinical remission, although this was only partial in the FCL. However, both subsequently relapsed, and the second patient with DLCL was refractory to radiotherapy and chemotherapy. In each case, the tumor-derived VH sequence was identified, and the CDR3 “clonal signature” was used to track tumor cell sequences in subsequent biopsies. All cases showed somatic mutations, with intraclonal heterogeneity evident at presentation, and some sequences were aberrant. The VH sequences of the DLCL which responded to treatment became homogeneous at relapse. The sequences of both the FCL and the refractory DLCL remained heterogeneous. In all cases, transcripts of multiple Ig isotypes could be identified, and there was immunophenotypic evidence for expression of several Ig isotypes. The case of refractory DLCL had identifiable transcripts from IgM, IgD, IgA, IgG, and IgE, but appeared to lose the ability to produce alternative isotype transcripts and protein at the late stage of disease. These cases indicate that VH gene analysis can be used to probe tumor cell behavior in cases of lymphoma and that perturbations caused by therapy and disease progression can occur.

787 Phase III clinical trial to test the safety and efficacy of autologous tumor lysate-loaded dendritic cells in patients with newly diagnosed glioblastoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A836-A836
Author(s):  
Marnix Bosch ◽  
Linda Liau ◽  
Keyoumars Ashkan
Keyword(s):  
Clinical Trial ◽  
Dendritic Cells ◽  
Tumor Cell ◽  
Disease Progression ◽  
Autologous Tumor ◽  
Newly Diagnosed ◽  
Tumor Lysate ◽  
Phase 3 ◽  
Link Type ◽  
To Receive

BackgroundGlioblastoma (GBM) is an incurable form of brain cancer with a high mortality rate in which multiple treatment attempts over the past decade have proven unsuccessful at extending survival. Early stage data have suggested that immunization against tumor cell antigens may be effective in GBM. In this Phase 3 study we aimed to assess whether autologous dendritic cells (DCs) loaded with autologous tumor cell lysate, is able to improve survival in these patients.MethodsWe conducted a randomized, double-blind, placebo-controlled international Phase 3 clinical trial with autologous tumor lysate-loaded DCs (DCVax-L) in 331 patients with histologically confirmed newly diagnosed GBM. Following surgery and chemoradiation, patients were randomized 2:1 to receive temozolomide plus DCVax-L or temozolomide plus placebo (i.e., autologous PBMC). Eligibility criteria included an intent for significant tumor resection (not biopsy only), sufficient doses of DCVax-L manufactured for 5 or more immunizations, and no radiographic evidence of apparent disease progression at the end of chemoradiation. A crossover option allowed all patients to receive the autologous vaccine at the time of disease progression. As a result, 90% of the randomized patients received DCVax-L at some point during their participation in the trial. Study subjects received immunizations with 2.5 million DCs or placebo at days 0, 10 and 20, followed by immunizations at months 2, 4, 8, 12, 18, 24 and 30. All subjects were assessed for progression-free survival(PFS) and overall survival (OS). This trial is registered with clinicaltrials.gov, number NCT00045968.Trial RegistrationThe study was registered as NCT00045968Ethics ApprovalThe study was approved by all applicable Institutional Review Boards or Ethics Committees

scholarly journals Modeling the effects of EMT-immune dynamics on carcinoma disease progression

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Daniel R. Bergman ◽  
Matthew K. Karikomi ◽  
Min Yu ◽  
Qing Nie ◽  
Adam L. MacLean
Keyword(s):  
Tumor Cell ◽  
Disease Progression ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Uterine Cancer ◽  
The Cancer Genome Atlas ◽  
Cell Phenotype ◽  
Free Survival ◽  
Mesenchymal Transition

AbstractDuring progression from carcinoma in situ to an invasive tumor, the immune system is engaged in complex sets of interactions with various tumor cells. Tumor cell plasticity alters disease trajectories via epithelial-to-mesenchymal transition (EMT). Several of the same pathways that regulate EMT are involved in tumor-immune interactions, yet little is known about the mechanisms and consequences of crosstalk between these regulatory processes. Here we introduce a multiscale evolutionary model to describe tumor-immune-EMT interactions and their impact on epithelial cancer progression from in situ to invasive disease. Through simulation of patient cohorts in silico, the model predicts that a controllable region maximizes invasion-free survival. This controllable region depends on properties of the mesenchymal tumor cell phenotype: its growth rate and its immune-evasiveness. In light of the model predictions, we analyze EMT-inflammation-associated data from The Cancer Genome Atlas, and find that association with EMT worsens invasion-free survival probabilities. This result supports the predictions of the model, and leads to the identification of genes that influence outcomes in bladder and uterine cancer, including FGF pathway members. These results suggest new means to delay disease progression, and demonstrate the importance of studying cancer-immune interactions in light of EMT.

scholarly journals VISTA: Virtual ImmunoSTAining for pancreatic disease quantification in murine cohorts

2020 ◽  
Author(s):  
Luke Ternes ◽  
Ge Huang ◽  
Christian Lanciault ◽  
Guillaume Thibault ◽  
Rachelle Riggers ◽  
...  
Keyword(s):  
Disease Progression ◽  
Animal Studies ◽  
Semantic Segmentation ◽  
Pancreatic Disease ◽  
Poor Quality ◽  
Pancreatic Tissue ◽  
Cancer Evolution ◽  
Histologic Feature ◽  
Stromal Compartment ◽  
Automated Platform

AbstractMechanistic studies of pancreatic disease progression using animal models require objective and quantifiable assessment of tissue changes among animal cohorts. Disease state quantification, however, relies heavily on tissue immunostaining, which can be expensive, labor- and time-intensive, and all too often produces uneven staining that is prone to variable interpretation between experts and inaccurate quantification. Here we develop a fully automated semantic segmentation tool using deep learning for the rapid and objective quantification of histologic features using hematoxylin and eosin (H&E) stained pancreatic tissue sections acquired from murine pancreatic cancer models. The tool was successfully trained to segment and quantify multiple histopathologic features of pancreatic pre-cancer evolution, including normal acinar structures, the ductal phenotype of acinar-to ductal metaplasia (ADM), dysplasia, and the expanding stromal compartment. Disease quantifications produced by our computational tool were highly correlated to the results obtained by immunostaining markers of normal and diseased tissue (DAPI, amylase, and cytokeratins; correlation score= 0.9, 0.95, and 0.91, respectively) and were able to accurately reproduce immunostain patterns. Moreover, our tool was able to distinguish ADM from dysplasia, which are not reliably distinguished by immunostaining, and avoid the pitfalls of uneven or poor-quality staining. Using this tool, we quantified the changes in histologic feature abundance for murine cohorts with oncogenic Kras-driven disease at 2 months and 5 months of age (n=12, n=13). The calculated changes in histologic feature abundance were consistent with biological expectations, showing an expansion of the stromal compartment, a reduction of normal acinar tissue, and an increase in both ADM and dysplasia as disease progresses (p= 2e-6, 6e-7, 4e-4, and 3e-5, respectively). These results demonstrate the tool’s efficacy for accurate and rapid quantification of multiple histologic features using an objective and automated platform. Our tool promises to rapidly accelerate and improve the quantification of altered pancreatic disease progression in animal studies.

Sign in / Sign up

Export Citation Format

Share Document